Basic carbonates and carbamates of benzopyrans

ABSTRACT

WHEREIN N IS 1 OR 2; R1 is hydrogen or loweralkyl; R2 is loweralkyl; R3 is alkyl or cycloalkyl; X is O or NH; y is an integer from 2-6; and R4 and R5 each are hydrogen or loweralkyl; or R4 and R5 taken together form a 5- or 6-membered heterocyclic ring and the acid addition salts thereof.   Basic carbonates and carbamates of benzopyrans represented by the formula

United States Patent Lee [ Dec. 16, 1975 BASIC CARBONATES AND CARBAMATESOF BENZOPYRANS Cheuk Man Lee, Waukegan, Ill.

Abbott Laboratories, North Chicago, Ill.

Filed: May 25, 1972 Appl. N0.: 256,954

Inventor:

Assignee:

US. Cl 260/345.3; 424/283; 260/243 B; 260/293.58; 260/247.2 A; 260/247.2B; 260/268 TR; 260/326.34

Int. Cl. C07D 311/80; CO7D 311/94 Field of Search 260/345.3

References Cited UNITED STATES PATENTS l/l97l Drummond et al 260/345.24/1973 Pars et aL 260/3453 Primary Examiner-John M. Ford Attorney,Agent, or FirmGildo E. Fato; Robert L. Niblack 57 ABSTRACT Basiccarbonates and carbamates of benzopyrans represented by the formulawherein n is l or 2; R is hydrogen or loweralkyl; R is loweralkyl; R isalkyl or cycloalkyl; X is O or NH; y is an integer from 2-6; and R and Reach are hydrogen or loweralkyl; or R and R taken together form a 5- or6-membered heterocyclic ring and the acid addition salts thereof.

11 Claims, No Drawings 1 BASIC CARBONATES AND CARBAMATES OF BENZOPYRANSDETAILED DESCRIPTION OF THE INVENTION This invention relates to basiccarbamates and carbonates of benzopyrans and to methods of making andusing the compounds.

The compounds of this invention are represented by the formula j OC-X-(CH )yN R I R 5 wherein n is l or 2; each R is hydrogen or loweralkyl; Ris loweralkyl; R is alkyl or cycloalkyl; X is O or NH; y is an integerfrom 26; and R and R each are hydrogen or loweralkyl; or R and R takentogether from a 5- or 6-membered heterocyclic ring and the acid additionsalts-thereof.

When n is l, the compounds are represented by the formula l R4\ R1 OC-X-(CH yN R I R1 When n is 2, the compounds are represented by the formulal R\\ oc-x-(cn )yN 4 l 2 5 methyl, cyclobutyl, cyclooctyl and the like.

The term a 5- or 6-membered heterocyclic ring includes pipen'dino,morpholino, thiomorpholino, piperazino, pyrroliclino and the like.

The term a pharmaceutically acceptable acid addition salt refers tonon-toxic salts prepared, for example, by reacting the basic carbamatesor carbonates with an organic or inorganic acid. Representative saltsinclude the hydrochloride, hydrobromide, sulfate, bisulfate, acetate,valerate, oleate, laurate, borate, ben- Zoate, lactate, phosphate,tosylate, citrate, maleate, fumarate, succinate, tartrate and the like.

The compounds of this invention exhibit central nervous system activityand are particularly useful as antianxiety agents at dosages of from 0.5to 30 mg./kg. of body weight daily. The combination of anti-depressantand transquilizing activity makes the compounds particularly useful intreating depressed patients wherein one of the manifested symptoms ofdepression is anxiety. The anti-depressant activity was established inthe modified dopa test. [Everett, The Dopa Response Potentiation Testand Its Use In Screening for Antidepressant Drugs, Excerpta MedicaInternational Congress Series No. 122, pp 164-167 (1966)].

In addition to the central nervous system activity, the compounds ofthis invention exhibit excellent activity asantihypertensive agents atdosages of from 0.1 to 10 mg./kg. of body weight daily. Theantihypertensive activity was first established in the spontaneouslyhypertensive rat procedure, Tabei et al., Clin. Phannac. and Therap.,11(2): 269-274 (1970). Hypertensive patients are often treated both withagents which lower blood pressure and with tranquilizers. Thecombination of both activities exhibited by the compounds of thisinvention makes them particularly useful iii the management ofhypertension.

The compounds also exhibit analgesic activity at dosages of from 40 tomg./kg.'of body weight daily. Thus, the compounds are additionallyuseful in treating the headaches associates with depression and/orhypertension.

Generally speaking, the carbonates of this invention are prepared byreacting the 9- or l-chlorocarbonyloxy derivative of the correspondingbenzopyran with the appropriate alcohol. The carbamates are prepared byreacting the 9- or l-chlorocarbonyloxy derivative of the correspondingbenzopyran with an appropriate dialkylamino (or heterocyclic)alkylamine. The acid addition salts can be prepared by reacting an organic orinorganic acid with the carbamate or carbonate.

The benzopyran starting compounds can be prepared by several well knownroutes such as that reported by Adams et al., J. Chem. Soc., 62, 2245and 2407 (1940) or Mechoulam et al., J. Am. Chem. Soc., 89, 4552 (1967).

The following examples further illustrate this invention.

EXAMPLE 1 9-(Chlorocarbonyloxy )-4,4-dimethyl-7-( 3-methyl-2- octyl)-1,2,3,4-tetrahydrocyclopenta[ c [l ]benzopyran on H OCCl

CH3 CH3 1 Q CH2 cu, cncnc ,n..+coci fin, CHCHC5H.,

] CGH" 0 CH3 cu, cu CH3 A solution of 3.42 g. (0.01 mole) of4,4-dimethyl-9- hydroxy-7-( 3methyl-2-octyl 1 ,2,3,4-tetrahydrocyclopenta[c][l ]benzopyran in 25 ml. of benzene was addeddropwise to a stirred solution of 8.7 g. of 12.5% phosgene in benzene(0.011 mole) cooled in an ice bath, followed by dropwise addition of asolution of 1.33 g. (0.011 mole) of N,N-dimethylaniline in ml. ofbenzene. The mixture was stirred in ice bath temperature for a while,then at room temperature overnight (18 hours). The mixture was heated inan oil bath at 7585 for 1 hour and evaporated to dryness in vacuo. Theresidue was triturated with ether; a solid separated, which was filteredoff. The filtrate was evaporated to dryness in vacuo giving 4.5 g. ofthe crude product as a dark viscous residue.

EXAMPLE 2 1 -(Chlorocarbony1oxy )-3-( 3-methyl-2-octyl )-6,6,9-trimethyl-7,8 ,9,10-tctrahydro-6H-dibenzo[b,d]pyran was preparedaccording to the method of Example 1 from 1-hydroxy-3-(3-methyl-2-octyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran.

EXAMPLE 3 9- {[2-( Diethylamino )ethoxy carbonyloxy -4,4- dimethyl-7-(3-methyl-2-octyl l ,2,3 ,4-tetrahydrocyclopenta[c] [1 ]benzopyran Asolution of 4.5 g. of crude 9-(chlorocarbonyloxy)-4,4-dimethyl-7-(3-methyl-2-octyl)-1,2,3 ,4-tetrahydrocyclopenta[c][l]benzopyran in 30 ml. of benzene was added dropwise to a stirredsolution of 2.11 g. of 2-(diethylamino)ethanol in 30 ml. of benzene. Themixture was stirred at room temperature for 16 hours and then refluxedfor 8 hours. The mixture was allowed to cool to room temperature and wasfiltered. The filtrate was evaporated to dryness in vacuo and theresidue was purified by chromatography on a 60-100 mesh Florisilactivated magnesium silicate column (150 g.). The column was firsteluted with chloroform and then with 5% methanol in chloroform to give1.25 g. of the pure product.

Analysis Calcd. for C H NO C, 74.18; H, 9.76. Found: C, 74.42; H, 9.73.

EXAMPLE 4 4,4-Dimethyl-9-{N-[ 3-(dimethylamino)propyl1carbamoyloxy}-7-(3-methyl-2-octyl 1 ,2,3 ,4-tetrahydrocyclopenta[c][1 ]benzopyran Asolution of 3.75 g. of crube9-(chlorocarbonyloxy)-4,4-dimethyl-7-(3-methyl-2-octyl-1,2,3,4-tetrahydrocyclopenta[c][1]benzopyran in 30 ml. of benzene was added dropwise to a stirredsolution of 1.73 g. of 3-(dimethylamino)propylamine in 30 ml. ofbenzene. The reaction mixture was cooled in an ice bath during theaddition and stirred at room temperature for 18 hours. The mixture wasthen filtered to remove the resulting solid material. The filtrate wasevaporated to dryness in vacuo to give 5.2 g. of dark residue. Theresidue was chromatographed on a 60-100 mesh Florisil activatedmagnesium silicate column (150 g.). The column was first eluted withchloroform, followed by 5% methanol in chloroform to give 2.15 g. of thepure product.

Analysis Calcd. for C H N O C, 74.00; H, 9.85; N 5.95. Found: C, 74.65;H, 10.18; N, 5.70.

EXAMPLE 5 4,4-Dimethyl-9- {N-[ 3-( l-methyl-4-piperazinyl)-propy1]carbamoyloxy}-7-( 3-methyl-2-octyl 1 ,2,3,4-tetrahydrocyclopenta[c][l ]benzopyran dimaleate, m.p. 191192 wasprepared according to the method of Example 4, using 3-(l-methyl-4-piperazinyl)- propylamine.

Analysis Calcd. for C H N O .2(C H O C, 63.39; H, 7.85 N, 5.54. Found:C, 63.50; H, 7,94; N, 5.49.

EXAMPLE 6 4,4-Dim ethyl-9- 2-( 1-methyl-4-pip erazinyl )ethoxy]carbonyloxy} -7-( 3-methyl-2-octyl 1 ,2,3,4-tetrahydrocyclopenta[c][l]benzopyran was prepared according to the method of Example 3 using 2-(l-methyl-3- piperazinyl)ethanol.

Analysis Calcd. for C ,H N O C, 72.62; H, 9.44; N, 5.46. Found: C,73.08; H, 9.54; N, 5.22.

EXAMPLE 7 4,4-Dimethyl-9- 2-( 1 -methyl-4-piperazinyl )ethoxy]carbonyloxy}-7-( 3-methyl-2-octyl)- 1 ,2,3,4-tetrahydrocyclopenta[c][l ]benzopyran difumate was prepared by reacting the compoundofExample 6 with f urmaric acid, m.p. 174176.

Analysis Calcd. for C H N O .2(C H O C, 62.88; H, 7.58; N, 3.77. Found:C, 62.76; H, 7.55; N. 3.77.

EXAMPLE 8 4,4-Dimethyl-9- {N-[ 3-(morpholino )propyl ]carbamoyloxy -7-(3-methy1-2-octyl 1 ,2 ,3 ,4-tetrahydrocyclopenta[c][1 ]benzopyran, wasprepared according to the method of Example 4, using 3-(m0rph0lino)-propylamine.

Analysis Calcd. for C N O C, 72.62; H, 9.44; N, 5.46. Found: C, 72.11;H, 9.41; N, 5.39.

EXAMPLE 9 5 6 and other therapeutically inert ingredients necessary in Acompound in accordance with claim 3: 4,4- the formulation of the desiredpreparation. dim y -l y )p py l I clai bamoyloxy}-7-( 3-methyl-2-octyl)-l ,2 ,3 ,4-tetrahyl. A compound of the formula y p l ll l py 5 S. Acompound in accordance with claim 2 wherein X is 0. 1 6. A compound inaccordance with claim 9-{[2- I (diethylamino)ethoxy]carbonyloxy}-4,4-dimethyl-7- (3-methyl-2-octyl)-l ,2,3,4-tetrahydrocyclopenta[c] [10C 2 Y 10 ]benzopyran or a pharmaceutically acceptable acid additionsalt thereof.

R5 7. A compound in accordance with claim 1 wherein n is 2 and thecompound is represented by the formula R3 R1 0 R l. C-X- CH N 2 1 2) yRS R R wherein n is 1 or 2; each R is hydrogen or loweralkyl; 2 R 3 R isloweralkyl, R is alkyl of from 1 to 20 carbon 2 atoms or cycloalkyl offrom 3 to 8 carbon atoms; X is O or NH; y is an integer from 26; and Rand R each 8. A compound in accordance with claim 7 of the forarehydrogen or loweralkyl, or a pharmaceutically acmllla ceptable acidaddition salt thereof.

2. A compound in accordance with claim 1 wherein CH (lJI R n is 1 andthe com ound is re t d b the formula p presen e y OC-X- (CH )yN 4 9. Acompound in accordance with claim 8 wherein X is NH.

10. A compound in accordance with claim 9: l-{N- [3-(dimethylamino)propyl ]carbamoyloxy} -3-( 3-me thyl-2-octyl )-6,6,9-trimethyl-7,8,9,10-tetrahydro-6l-ldibenzo[b,d]pyran or a pharmaceutically acceptableacid addition salt thereof.

11. A compound in accordance with claim 10 3. A compound in accordancewith claim 2 wherein wherein X is O. X is NH.

1. A COMPOUND OF THE FORMULA
 2. A compound in accordance with claim 1wherein n is 1 and the compound is represented by the formula
 3. Acompound in accordance with claim 2 wherein X is NH.
 4. A compound inaccordance with claim 3:4,4-dimethyl-9-(N-(3-(dimethylamino)propyl)carbamoyloxy)-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta(c)( l )benzopyran.
 5. A compound inaccordance with claim 2 wherein X is O.
 6. A compound in accordance withclaim 5:9-((2-(diethylamino)ethoxy)carbonyloxy)-4,4-dimethyl-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta(c)( l )benzopyran or a pharmaceuticallyacceptable acid addition salt thereof.
 7. A compound in accordance withclaim 1 wherein n is 2 and the compound is represented by the formula 8.A compound in accordance with claim 7 of the formula
 9. A compound inaccordance with claim 8 wherein X is NH.
 10. A compound in accordancewith claim 9:1-(N-(3-(dimethylamino)propyl)carbamoyloxy)-3-(3-methyl-2-octyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo(b,d)pyran or apharmaceutically acceptable acid addition salt thereof.
 11. A compoundin accordance with claim 10 wherein X is O.